S200: IMPROVED OVERALL SURVIVAL WITH FIRST-LINE BRENTUXIMAB VEDOTIN PLUS CHEMOTHERAPY IN PATIENTS WITH STAGE III/IV CLASSICAL HODGKIN LYMPHOMA: 6-YEAR ANALYSIS OF ECHELON-1
Authors: M. Hutchings, S. M. Ansell, D. J. Straus, J. M. Connors, W. S. Kim, A. Gallamini, R. Ramchandren, J. W. Friedberg, R. Advani, A. M. Evens, P. Smolewski, K. J. Savage, N. L. Bartlett, H.-S. Eom, J. S. Abramson, C. Dong, F. Campana, K. Fenton, M. Puhlmann, J. Radford
Journal: HemaSphere (2022)

Background: In classical Hodgkin lymphoma (cHL), improved overall survival (OS) with first-line treatment using new combinations has seldom been observed compared with existing approaches. Five-year data from the randomized phase 3 ECHELON-1 study (NCT01712490) supported long-term progression-free survival (PFS) with brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), in patients (pts) with previously untreated stage III/IV cHL, regardless of interim positron emission tomography (PET) status. The long-term safety profile of A+AVD was manageable, and numerically fewer secondary malignancies were reported versus ABVD, as well as a greater number of pregnancies (Straus et al, Lancet Haematol 2021). Aims: To report the pre-specified OS analysis from ECHELON-1, as well as relevant long-term safety data, after approximately 6 years of follow-up (cut-off June 1, 2021). Methods: Pts were randomized 1:1 to receive up to 6 cycles of A+AVD (n=664) or ABVD (n=670) on day 1 and 15, every 28 days. PFS per investigator was reported for long-term follow-up. The key secondary end point was OS, which was an event-driven, pre-specified, alpha-controlled analysis in the intention-to-treat population, with a prespecified interim analysis after 103 deaths. Analysis of OS in prespecified subgroups was exploratory and was not adjusted for multiplicity. Informed consent was obtained for all pts. Results: In total, 39 OS events in the A+AVD arm and 64 in the ABVD arm had occurred at a median follow-up of 73 months, significantly favoring A+AVD (hazard ratio [HR] 0.590; 95% CI 0.396–0.879; p=0.009). There was a consistent OS benefit for A+AVD vs ABVD across prespecified subgroups, including: stage III (HR: 0.863; 95% CI 0.452–1.648) and stage IV disease (HR: 0.478; 95% CI 0.286–0.799) at diagnosis, pts who were PET-negative at cycle 2 (PET2)-negative (HR: 0.583; 95% CI 0.338–0.856) and PET2-positive (HR: 0.163; 95% CI 0.037–0.717), pts aged <60 years (HR: 0.509; 95% CI 0.291–0.890), pts aged ≥60 years (HR: 0.829; 95% CI 0.469–1.466), and across all geographies, including Europe (HR: 0.783; 95% CI 0.467–1.315) and North America (HR: 0.327; 95% CI 0.153–0.699). The 6-year PFS estimate was 82.3% (79.1–85.0) vs 74.5% (70.8–77.7) with A+AVD vs ABVD, respectively (HR: 0.678; 95% CI: 0.532–0.863). The long-term safety profile of A+AVD was comparable to that of ABVD. In both A+AVD and ABVD groups, treatment-emergent peripheral neuropathy continued to resolve or improve, with 86% (379/443) and 87% (249/286) of cases in the A+AVD and ABVD arms either completely resolving (72% vs 79%) or improving (14% vs 8%) by last follow-up. Overall, 23 secondary malignancies in the A+AVD arm and 32 in the ABVD arm were reported. Pregnancies and live births were reported by a greater number of female pts in the A+AVD group vs the ABVD group (49 vs 28 and 42 vs 19, respectively) and there were no stillbirths reported during the study. There were no new safety signals. Summary/Conclusion: There was a statistically significant 41% reduction in the risk of death with A+AVD vs ABVD, with a consistent OS benefit across prespecified subgroups. The long-term safety profile was manageable, consistent with prior reports. These data support A+AVD as a preferred option for previously untreated stage III and IV cHL.